The present invention relates to new metalloprotease inhibitors and to pharmaceutical compositions containing them.
In the physiological state, the synthesis of connective tissues is in dynamic equilibrium with the degradation of the extracellular matrix. That degradation is due to zinc proteases (metalloproteases) secreted by the cells of the existing matrix: they are, without implying any limitation, collagenases (MMP-1, MMP-8, MMP-13), gelatinases or collagenases of type IV (MMP-2, MMP-9) and stromelysins (MMP-3).
In the normal state, those catabolic enzymes are regulated in terms of their synthesis and their secretion, and in terms of their extracellular enzymatic activity, by natural inhibitors, such as xcex12-macroglobulin or the TIMPs (Tissue Inhibitors of MetalloProteinases), which form inactive complexes with the metalloproteases.
A common factor in pathologies in which those enzymes are implicated is an imbalance between the activity of the activated enzymes and that of their natural inhibitors, the consequence of which is excessive tissue degradation.
Uncontrolled and accelerated membrane degradation by resorption of the extracellular matrix catalysed by the metalloproteases is a parameter common to a number of pathological conditions, such as rheumatoid arthritis, arthrosis, tumour invasion and growth, including malignant spread and the formation of metastases, ulcerations, atherosclerosis, etc.
BB94, a metalloprotease inhibitor, has recently exhibited anti-tumour activity in clinical use, where it has proved to be active against ovarian cancers (Becket el al., DDT 1996. 1 (1), 16).
It may therefore be expected that a metalloprotease inhibitor will restore the equilibrium between protease and inhibitor and thus favourably modify the development of such pathologies.
A certain number of metalloprotease inhibitors have been described in the literature. There should be mentioned, more especially, the compounds described in Patent Specifications WO 95/35275, WO 95/35276, EP 606 046, WO 96/00214 and EP 803 505.
The compounds of the present invention are not only new but have also proved to be more powerful metalloprotease inhibitors than those described in the literature, thus making them potentially useful in the treatment of cancer, rheumatic diseases, such as arthrosis and rheumatoid arthritis, atherosclerosis, etc.
More specifically, the present invention relates to compounds of formula (I): 
wherein:
R1 represents a hydrogen or halogen atom, or a linear or branched (C1-C6)alkyl or linear or branched (C1-C6)alkoxy group,
R2 represents a hydroxy, linear or branched (C1-C6)alkoxy or xe2x80x94NHOH group,
Ar1 represents a phenylene or biphenylene group,
X represents an oxygen or sulphur atom, an NR group, a xe2x80x94Cxe2x89xa1Cxe2x80x94 group or a bond,
R represents a hydrogen atom or a linear or branched (C1-C6)alkyl group,
n is an integer from 0 to 6 inclusive,
Ar2 represents:
a phenyl group substituted by a heteroaryl group,
a biphenyl group substituted by a heteroaryl group,
a pyridinyl group substituted by a heteroaryl group, or
a heterocyclic group,
their isomers and addition salts thereof with a pharmaceutically acceptable acid or base, it being understood that
xe2x80x9cheteroaryl groupxe2x80x9d is understood to mean a mono-cyclic aromatic group- or bi-cyclic aromatic group wherein at least one cycle is aromatic containing one, two or three identical or different hetero atoms selected from nitrogen, oxygen and sulphur, optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, linear or branched trihalo-(C1-C6)alkyl, linear or branched trihalo-(C1-C6)alkoxy, and hydroxy,
xe2x80x9cheterocyclic groupxe2x80x9d is understood to mean a saturated or partially saturated, mono- or bi-cyclic non-aromatic group containing one, two or three identical or different hetero atoms selected from nitrogen, oxygen and sulphur, optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, linear or branched trihalo-(C1-C6)alkyl, linear or branched trihalo-(C1-C6)alkoxy, and hydroxy.
Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The preferred heteroaryl groups are the imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidyl, triazolyl, pyrazolyl and benzimidazolyl groups.
The preferred heterocyclic groups are the pyrrolidinyl, morpholino, piperidino, imidazolidinyl, thiazolidinyl, oxazolidinyl, piperazinyl, isoindolyl, 2,3-dihydroisoindolyl and cyclopenta[c]pyrrolidinyl groups.
The preferred compounds of the invention are the compounds of formula (I) wherein X represents an oxygen atom or a sulphur atom.
The preferred R1 group is the hydrogen atom.
The preferred R2 group is the xe2x80x94NHOH group.
When Ar1 represents a phenylene group, n is more especially zero.
When Ar1 represents a phenylene group, Ar2 preferably represents a phenyl group substituted by a heteroaryl group, the heteroaryl group preferably being an imidazolyl, triazolyl or pyridinyl group.
More especially, the preferred compounds of the invention are the compounds of formula (I) wherein Ar1 represents a phenylene group, X represents an oxygen or sulphur atom, n is zero, and Ar2 represents a phenyl group substituted by a heteroaryl group selected from imidazolyl, triazolyl and pyridinyl.
When Ar1 represents a biphenylene group, Ar2 preferably represents a heterocyclic group.
The configuration of the 4,5,6,7-tetrahydrofuro[2,3-c]pyridine ring is preferably (5R).
The preferred compounds of the invention are:
6- {4-[4-(imidazol-1-yl)phenoxy]benzenesulphonyl}-4,5,6,7-tetrahydrofuro[2,3-c]-pyridine-(5R)-(N-hydroxy)carboxamide, and its corresponding addition salts,
6-{4xe2x80x2-[2-(pyrrolidin-1-yl)ethoxy]biphenyl-4-sulphonyl}-4,5,6,7-tetrahydrofuro[2,3-c]-pyridine-(5R)-(N-hydroxy)carboxamide, and its corresponding addition salts,
6-{4-[4-(1,3,4-triazol-1-yl)phenoxy]benzenesulphonyl}-4,5,6,7-tetrahydrofuro[2,3-c]-pyridine-(5R)-(N-hydroxy)carboxamide, and its corresponding addition salts,
6-{4-[4-(pyridin-4-yl)phenoxy]benzenesulphonyl}-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-(5R)-(N-hydroxy)carboxamide, and its corresponding addition salts,
6-{4-[(4-(1,3,4-triazol-1-yl)phenylthio]benzenesulphonyl}-4,5,6,7-tetrahydrofuro[2,3-c]-pyridine-(5R)-(N-hydroxy)carboxamide, and its corresponding addition salts.
The invention relates also to a process for the preparation of compounds of formula (I), characterised in that there is used as starting material a compound of formula (II), in racemic form or in the form of a specific isomer: 
wherein R1 is as defined for formula (I), and Rxe2x80x2 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, the amine function of which is substituted by a halogen compound of formula (III):
ClSO2xe2x80x94Ar1xe2x80x94Xxe2x80x94(CH2)nxe2x80x94Ar2xe2x80x83xe2x80x83(III)
wherein Ar1, X, n and Ar2 are as defined for formula (I), to yield:
when Rxe2x80x2 represents a hydrogen atom, a compound of formula (I/a), a particular case of the compounds of formula (I): 
wherein R1, Ar1, X, N and Ar2 are as defined hereinbefore,
or, when Rxe2x80x2 represents a linear or branched (C1-C6)alkyl group (Rxe2x80x3), a compound of formula (I/a1), a particular case of the compounds of formula (I): 
wherein R1, Ar1, X, n, Ar2 and Rxe2x80x3 are as defined hereinbefore,
which may be subjected to the action of an acid, to yield a compound of formula (I/a) described hereinbefore,
*which compound of formula (I/a):
is subjected, if desired, to the action of an O-substituted hydroxylamine, to yield, after deprotection of the hydroxylamine function, a compound of formula (I/b). 
wherein R1, Ar1, X, n and Ar2 are as defined hereinbefore,
*which compounds of formulae (I/a), (I/a1) and (I/b) constitute the totality of the compounds of formula (I),
which are purified, if necessary, according to a conventional purification technique, are separated, where appropriate, into their isomers according to a conventional separation technique, and are converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base. The compounds of formulae (11) and (III) are either commercial products or are obtained according to known procedures.
The invention relates also to pharmaceutical compositions comprising as active ingredient one compound of formula (I) with one or more suitable inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous or sub-cutaneous) or nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions, etc.
The useful dosage can be adapted according to the nature and severity of the disorder, the route of administration and according to the age and weight of the patient, and may vary from 0.01 to 2 g per day in one or more administrations.